The objective of this work is the development of a flexible, high performance, dedicated breast PET-DBT scanner that is used in early-stage primary tumor characterization, in diagnostic imaging of patients with suspicious, early-stage cancer, as well as in assessing tumor response to therapy. The design allows full integration of a high performance breast PET scanner with a DBT unit for multi-modality imaging. In order to achieve this objective the dedicated scanner will be developed to provide quantitative PET images with fully corrected data co-registered with DBT images. Commercial whole-body PET/CT scanners are limited in their performance when imaging small (< 2 cm in size), early stage tumors or for detecting small changes in tumor uptake. Dedicated breast PET scanners, on the other hand, have been geared more towards lesion detection (patient screening) and do not emphasize the quantitative imaging capability of these systems that is needed for personalized therapy. Our aims are to: (i) develop a high spatial resolution and high sensitivity, quantitative breast PET scanner that is integrated with a DBT system, (ii) conduct pilot clinical studies to characterize early stage breast cancer and perform diagnostic imaging in patients with dense breasts, and (iii) help determine role of high performance, dedicated breast PET-DBT in personalized breast cancer treatment. The clinical studies will involve two clinical scenarios: characterization of early stage, ER+ breast cancer using 18F- fluoroestradiol, and diagnostic 18F-fluordeoxyglucose imaging in patients with dense breasts. In the first aim we will complete a full assembly of the PET-DBT device with a dedicated data acquisition system and customized gantry. In the second and third aims we will first optimize data correction and calibration techniques that have been developed for image quantitation, followed by system characterization and optimization for clinical imaging. In the fourth aim we plan on performing two clinical studies (each with up to 20 patients) to compare and correlate quantitative results from the dedicated breast PET scanner to those obtained from whole-body PET, as well as in vitro results from pathology. At the end of the study we expect to have demonstrated the role a high resolution, dedicated breast PET-DBT scanner can play in the future for personalized breast cancer treatment.